Allogeneic hematopoietic cell transplant continues to be associated with a high morbidity and mortality. Fifteen to 50% of patients die from complications related to the procedure. Graft-versus-host disease (GVHD) affects 20-80% of transplant recipients and is the major cause of post transplant non-relapse mortality. While some clinical parameters (e.g. age, donor: recipient histocompatibility) can predict GVHD, no biological factors have been identified that reliably predict the incidence and severity of GVHD and its associated mortality, as well as allow an understanding of the underlying pathogenesis of the disease, which, in turn could inform innovative treatment approaches. Hence, there exists a critical need to identify reliable biomarkers for the disease. We hypothesize that polymorphisms in genes regulating biological pathways of GVHD are associated with GVHD and transplant related mortality (TRM). We propose a candidate gene approach to analyze, in 838 subjects (donors and recipients), the relationship of 427 genetic polymorphisms which may modulate the immune response, inflammatory amplification and the metabolism of therapeutic agents with the incidence and course of GVHD and transplant related mortality. We will use conventional multiple variable regression analysis to identify relevant polymorphisms and will test novel machine based learning and graph based algorithms to identify gene patterns or interactions not recognizable with usual statistical techniques. Reliable genetic biomarkers would permit identification of high risk patients who need more effective prophylaxis or preemptive screening or therapeutic interventions to limit the severity of their graft versus host disease and ultimately to improve survival. Validation of our findings in a subsequent multicenter cohort could provide important data useful to inform the management of allograft patients and improve their outcomes. PUBLIC HEALTH RELEVANCE Graft-versus-host disease is a devastating disease that affects 20-70% of blood and marrow transplant (BMT) recipients. The disease is caused by an immune attack by donor cells on patient tissue. Some genetic factors, including polymorphisms (changes in amino acids in genes that alter their function) may predict patients at high risk of these complications. We aim to identify patients at high risk of complications and death, and subsequently modify their treatment, using the information we learn from our genetic studies, to alter their course. Our long term goal is to improve survival in these patients by determining groups at high risk towards whom intensive therapy should be targeted.